The application of solid-phase combinatorial chemistry and parallel synthesis techniques for the preparation of non-peptide drug-like molecules has greatly expanded the diversity of agents available for biological screening in the pharmaceutical industry. There has been considerable effort to increase the size and diversity of corporate sample collections to feed HTS (high throughput screening) programs. HTS can potentially deliver a plethora of lead structures, active in novel therapeutic targets, for the medicinal chemist to explore. While there have been many reports in the literature describing methods to prepare acyclic and cyclic (5-, 6- and 7-membered cycles and fused-cycles) compound libraries for HTS; as well as for lead optimization programs, there has been few reports describing the solid-phase synthesis of macrocylic compound libraries..sup.1 To achieve a truly diverse sample collection for screening, it is desirable that the sample collection contain molecules of varying degrees of conformational flexibility as listed in table I.
TABLE I Conformational Molecules Flexibility Examples Acyclic High oligonucleotides.sup.1a, peptides.sup.1b, peptoids.sup.1c, b-peptoids.sup.1d, oligocarbamates.sup.1e Macrocyclic Medium cyclic peptides.sup.1f, macrocycles.sup.1g Cyclic Low benzodiazepines.sup.1h, hydantoins.sup.1i, diketopiperazines.sup.1j, 2- alkylthiobenzimidazoles.sup.1k
Acyclic molecules, because they can adopt multiple low energy conformations, would be expected to be fairly promiscuous and provide a higher hit rate relative to the more restricted molecules. Acyclics; however, provide little information about the required spatial arrangement of pharmacophoric groups. On the other hand, cyclic conformationally restricted molecules would be expected to provide valuable structural information concerning the binding requirements. Macrocylic compounds, neither completely rigid nor flexible, would be unique in their coverage of 3-d space and would be a valuable addition to our sample collection. The fact that cyclic peptides have long been of interest due to their attractive biological profile provides further incentive for synthetic investigation. It has been well documented that cyclic peptides often display increased selectivity, better bioavailability, and less susceptibility to proteolytic degradation than corresponding polypeptides. The preparation of cyclic peptides on a solid support has been established as an efficient method of synthesis that avoids undesired cross coupling reactions common to macrocyclization by providing a "pseudo-diluted" environment..sup.2